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  • 1
    Electronic Resource
    Electronic Resource
    Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors (1996)
    Springer
    Cancer chemotherapy and pharmacology 38 (1996), S. 335-342 
    Details
    ISSN: 1432-0843
    Keywords: Key words Gemcitabine ; Colon cancer ; Continuous infusion ; schedule dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  2′,2′-Difluorodeoxycytidine (gemcitabine) is a cytidine analogue with established antitumor activity against several experimental tumor types and against human ovarian and non-small-cell lung cancer. Both preclinical studies and most clinical trials involving patients with solid tumors have focused on short-term administration schedules; however, mechanistic studies indicate that a continuous-infusion schedule may be more effective. We determined the maximal tolerated dose (MTD) of gemcitabine in mice using various schedules. At these MTDs we observed considerably better antitumor activity of gemcitabine in two of three murine colon carcinoma lines using a prolonged administration as compared with a standard bolus protocol (i.p. 120 mg/kg q3d×4). On the latter schedule, Colon 26–10 grown in BALB/c mice was the most sensitive tumor line, showing a growth-delay factor (GDF, number of doubling times gained by the treatment) of 6.7, whereas Colon 38 (grown in C57/B16 mice) was the least sensitive tumor, displaying a GDF of 0.9. Prolonged treatment (q3d×6) of Colon 26–10 at a lower dose (100 mg/kg) enhanced the antitumor activity (GDF 9.6) while producing similar toxicity. A similar weight loss was found following the continuous infusion (c.i.) of gemcitabine using Alzet osmotic pumps s.c. for 3 or 7 days (2 mg/kg), but the GDF increased to 2.4 in Colon 38 (C57/B16) as compared with that provided by the bolus injections. Continuous infusion of gemcitabine at 15 mg/kg per 24 h q7d×2 i.v. via the tail vein was more effective than bolus injection against Colon 26–10, with the GDF being 〉17.7 and 73% of the tumors regressing completely. However, against Colon 38 tumors this schedule was not effective (GDF 0.4), even with a 25% higher dose. The plasma pharmacokinetics of gemcitabine was determined after one bolus dose (120 mg/kg). The peak concentration of gemcitabine was 225 μM and that of the deaminated catabolite 2′,2′-difluorodeoxyuridine (dFdU) was 79 μM. The elimination of gemcitabine was much faster than that of dFdU, with the t 1/2ß values being 15 min and 8 h, respectively. For the c.i. schedules, plasma concentrations were below the detection limit of the assay (〈0.5 μM). Our results suggest that prolonged infusion of gemcitabine can give a better antitumor activity than bolus injections and shows promise of being active in clinical trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050492
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  • 2
    Electronic Resource
    Electronic Resource
    Tumor size and origin determine the antitumor activity of cisplatin or 5-fluorouracil and its modulation by leucovorin in murine colon carcinomas (1996)
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 79-89 
    Details
    ISSN: 1432-0843
    Keywords: Key words Tumor size ; Tumor origin ; Cisplatin ; 5-Fluorouracil ; Leucovorin modulation ; Antitumor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  5-Fluorouracil (FUra) is one of the few effective agents in the treatment of patients with colorectal cancer. Its effects on the target enzyme thymidylate synthase (TS) can be modulated by leucovorin (LV) or cisplatin (CDDP). Tumor size and differentiation of tumor characteristics can influence therapeutic efficacy. We therefore studied the relationship between tumor size (cutoff point 200 mm3) and the antitumor activity of FUra and its modulation by LV in murine Colon 26 and Colon 38 tumors. The doubling time of tumors measuring 〉200 mm3 was about 160% longer. The antitumor effect of FUra in these large tumors was decreased and could not be modulated by LV. In addition, three subtypes of Colon 26 (Colon 26-A, Colon 26-B, and Colon 26-10) were identified and characterized for tumor-induced weight loss, TS activity, response to chemotherapy, and histological features. Mice bearing Colon 38 and Colon 26-10 did not lose weight as a result of tumor growth. Colon 26-A caused a weight loss of up to 19%, whereas mice with Colon 26-B tumors remained within 10% of their initial weight and tolerated at least 2.5 times more tumor load than did mice bearing Colon 26-A, which induces cachexia. Among untreated tumors, TS catalytic activity was highest in Colon 26-B (5536 pmol mg protein-1 h-1) and lowest in Colon 38 (799 pmol mg protein-1 h-1); Colon 26-A and Colon 26-10 had intermediate activities (about 2500 pmol mg protein-1 h-1). 5-Fluoro-2′-deoxyuridine monophosphate (FdUMP) binding was comparable in the three Colon 26 subtypes but was lower in Colon 38. The antitumor activity of FUra could be modulated by LV in Colon 38, Colon 26-10, and Colon 26-A but could not in Colon 26-B, with complete responses (CR) being obtained in Colon 26-10 and Colon 38. The latter two were highly sensitive to CDDP, followed by Colon 26-A and Colon 26-B (CRs: 50%, 40%, 25%, and 0, respectively). Furthermore, necrosis was noted in Colon 26-B and Colon 38 but not in Colon 26-A. In conclusion, (1) the antitumor activity of FUra in large tumors is decreased and cannot be modulated by LV and (2) characteristics and sensitivity to chemotherapeutics can vary substantially in closely related tumors of the same origin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050541
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Biochemical consequences of 5-fluorouracil gastrointestinal toxicity in rats; effect of high-dose uridine (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 243-248 
    Details
    ISSN: 1432-0843
    Keywords: 5-Fluorouracil ; Gastrointestinal toxicity ; Uridine ; Biochemical modulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Selective protection of the normal host tissues from the toxic effects of anticancer agents would allow the use of higher, probably more effective, doses of the drugs. It has been demonstrated that delayed high-dose uridine administration after 5-fluorouracil decreases the extent of myelosuppression and causes faster regeneration of the bone marrow. We studied the biochemical consequences of the gastrointestinal toxicity caused by 5-fluorouracil and the potential of high-dose uridine treatment to influence these adverse effects. 5-Fluorouracil caused dose-related decreases in the biochemical parameters (thymidine kinase, sucrase, maltase, alkaline phosphatase) selected as early markers of the impaired metabolic activity of the intestinal mucosa. The nadir of the biochemical changes was reached between 24 h and 72 h after 5-fluorouracil treatment, and complete regeneration of the mucosa took 6–7 days. Delayed high-dose uridine administration failed to mitigate the severity of the gastrointestinal damage that ensued after 5-fluorouracil treatment, but caused significantly earlier regeneration of the mucosa.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685843
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    Paper (German National Licenses)
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